The skin consists of the outermost stratum corneum, epidermis, dermis, and subcutaneous connective tissues. Normally, the stratum corneum, which consists of layers of dead cells and lipid bilayers, exhibits a strong barrier function against numerous substances. Antigen-presenting cells called Langerhans cells are present in the dermal layer and serve immunological functions. Langerhans cells capture protein antigens invaded into the skin, degrade them within the cells, and display peptide fragments on the MHC molecules. MHC-peptide complexes migrate from the afferent lymph vessel to the subcortical layer of the regional lymph node, where they come into contact with T-cells via interdigitating cells. As Langerhans cells migrate in this way, antigens are conveyed to TH cells residing in the lymph node. Langerhans cells have MHC class II molecules, which are necessary for presenting antigens to TH cells.
Although vaccine administration into the dermis is known to be effective, owing to the strong barrier function of the stratum corneum of the skin as described above, there is a problem of accuracy associated with administration into the dermis that has limited thickness of 300 to 2000 μm using an injection needle due to technical difficulty.
As means for solving the above problem, microneedles have been developed. Microneedles of various sizes and shapes (extremely small projections having a height of approximately several tens to several hundreds micrometers) have been developed for the purpose of puncturing the outermost stratum corneum, which are anticipated to serve particularly as a method of noninvasive vaccine administration.
Also, various methods of drug application using a device with microneedles have been developed. For example, a method of administering a drug coated on the surface of microneedles, a method of forming a hole (a hollow needle) or a groove on a needle to allow a drug or a biological component to penetrate therethrough, and a method of incorporating a drug into a needle itself are proposed. In the light of the fact that all of these microneedle devices are equipped with extremely small projections having a height of approximately several tens to several hundreds micrometers (microneedles), transcutaneous absorbability and absorption efficiency of a drug are considered to be greatly varied depending on the method of drug application.
For example, as a method for efficiently promoting the transcutaneous absorbability of antigens (vaccines) using a microneedle, a method of coating a part of the microneedle surface with a drug is disclosed in, for example, Non Patent Literature 1. It indicates that when a part of a microneedle (particularly, only the needle part) is coated with antigens (vaccines), all or nearly all of the applied antigens (vaccines) are delivered into the body, hence the above method is useful as means for accurate intradermal administration.
Meanwhile, recently, the importance of efficient and safe administration of medicinal substances such as a diagnostic agent and a drug has been recognized. Particularly these days, as a countermeasure for a new strain of the influenza virus, development of a prepandemic vaccine (A/H5N1 subtype) is in progress (Non Patent Literature 2). In a vaccination method of this vaccine, subcutaneous or intramuscular vaccination has to be given twice, three weeks apart. In consideration of the pandemic of this type of new strain of the influenza virus, induction of immunity in as many people as possible with as little vaccine as possible becomes a challenge. For this, development of an efficient and simple method of vaccine administration is demanded.
Further, the “influenza HA vaccine”, which satisfies the minimum requirements for biological products as provided in the Japanese Pharmacopoeia, is widely used as an influenza vaccine at present in Japan. It is a trivalent vaccine containing type A (H1N1), type A (H3N2), and type B. As the dosing regimen, the vaccine has to be given by a subcutaneous injection once, or twice, one to four weeks apart. It is known that, in the rare occasion, there are still some people in whom the immunity is not easily induced. For this reason also, efficient vaccine administration is necessary.
A microneedle preparation using an influenza vaccine is disclosed in Patent Literature 1. While the disclosure regarding the microneedle preparation includes the administration method and the formulation of the influenza vaccine, a relationship between the dose of antigens administered by microneedles and the effect (antibody titer) is not examined at a dose equal to or less than that administered using an intramuscular injection (IM) or a subcutaneous injection (Sc). Further, no measures for reducing the dose of antigens and enhancing the effect are discussed.
Patent Literature 2 discloses a method of transcutaneous immunostimulation in which, after an influenza vaccine is administered orally, intranasally, by an injection, an adjuvant is applied to the skin surface. Although the above document exemplifies the administration methods involving oral, skeletal muscular, and subcutaneous routes, etc., it does not describe the administration using microneedles.
Patent Literature 3 discloses the administration using hollow microneedles with an aim to reduce the amount of therapeutic substances while achieving the therapeutic effect; however, there is no description relating to the induction of the immunity.